Cesium carbonate → Tert-butyl 4-[(6-bromo-2-{[1-({[tert-butyl(dimethyl)silyl]oxy}methyl)cyclopropyl]methyl}-1-oxo-1,2-dihydroisoquinolin-4-yl)sulfonyl]-1,4-diazepane-1-carboxylate

HRID 906454Notes

Reaction equation

HRID 906454 reaction equation
[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][CH:6]=[C:5]2[S:13]([N:16]1[CH2:22][CH2:21][CH2:20][N:19]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:18][CH2:17]1)(=[O:15])=[O:14].CS(O[CH2:35][C:36]1([CH2:39][O:40][Si:41]([C:44]([CH3:47])([CH3:46])[CH3:45])([CH3:43])[CH3:42])[CH2:38][CH2:37]1)(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:35][C:36]1([CH2:39][O:40][Si:41]([C:44]([CH3:47])([CH3:46])[CH3:45])([CH3:43])[CH3:42])[CH2:37][CH2:38]1)[CH:6]=[C:5]2[S:13]([N:16]1[CH2:22][CH2:21][CH2:20][N:19]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:18][CH2:17]1)(=[O:14])=[O:15]

Participants

6

Reactant 3

HCID 10796Cesium carbonateHCID 59000927[1-({[tert-Butyl(dimethyl)silyl]oxy}methyl)cyclopropyl]methyl methanesulfonateHCID 67391050HCID 67391050, compound

Product 1

HCID 67390814Tert-butyl 4-[(6-bromo-2-{[1-({[tert-butyl(dimethyl)silyl]oxy}methyl)cyclopropyl]methyl}-1-oxo-1,2-dihydroisoquinolin-4-yl)sulfonyl]-1,4-diazepane-1-carboxylate

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6228DimethylformamideSolvent

Procedure

tert-Butyl 4-[(6-bromo-1-oxo-1,2-dihydroisoquinolin-4-yl)sulfonyl]-1,4-diazepane-1-carboxylate (Example 46b, 0.40 g), [1-({[tert-butyl(dimethyl)silyl]oxy}methyl)cyclopropyl]methyl methanesulfonate (0.24 g) and cesium carbonate (0.536 g) were stirred together in DMF (20 mL) at 110° C. for 72 h under nitrogen, cooled to room temperature, diluted with water (100 mL) and extracted into ethyl acetate (3×20 mL). The combined organics were washed with saturated brine (3×20 mL), dried (MgSO4) filtered and evaporated, and the residue was purified (SiO2 chromatography, elution with 10% ethyl acetate in DCM) to give (tert-butyl 4-[(6-bromo-2-{[1-({[tert-butyl(dimethyl)silyl]oxy}methyl)cyclopropyl]methyl}-1-oxo-1,2-dihydroisoquinolin-4-yl)sulfonyl]-1,4-diazepane-1-carboxylate) as a solid. This was dissolved in DMF (10 mL), treated with N-cyclopropyl-3-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (0.089 g), potassium carbonate (0.077 g) and Pd-118 (0.006 g) and the resulting mixture was stirred at 70° C. under nitrogen for 1 h. After being cooled to room temperature, it was diluted with saturated brine and extracted into ethyl acetate (3×30 mL). The combined extracts were washed with brine (3×30 mL), dried (MgSO4) filtered and evaporated. The residue was dissolved in THF (20 mL), treated with 4 M HCl in dioxane (3 mL), stirred at room temperature for 3 h, evaporated and purified by preparative HPLC (Waters Xbridge column using a 95-5% gradient of aqueous 0.2% ammonia in acetonitrile as eluent) to give the title compound (0.019 g) as a solid.

Workup

  1. extractionextracted into ethyl acetate (3×20 mL)
  2. washThe combined organics were washed with saturated brine (3×20 mL)
  3. dry with materialdried (MgSO4)
  4. filtrationfiltered
  5. customevaporated
  6. customthe residue was purified
  7. wash(SiO2 chromatography, elution with 10% ethyl acetate in DCM)

Sources & evidence

ORD record
ord-a11324419ef14c5484143e854cb51c46
Source dataset
uspto-grants-2011_09
Patent number
US08012980B2

Reaction notes

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